chr17-39665182-G-T

Variant names:

• chr17-39665182-G-T
• rs931992
• NM_003673.4:c.-178G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003673.4(TCAP):​c.-178G>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.614 in 629,156 control chromosomes in the GnomAD database, including 125,022 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (23698 hom., cov: 33)
  • Exomes 𝑓: 0.64 (101324 hom.)
• Consequence: TCAP NM_003673.4 upstream_gene
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0460
• Publications: 37 publications found

Genes affected

TCAP (HGNC:11610): (titin-cap) Sarcomere assembly is regulated by the muscle protein titin. Titin is a giant elastic protein with kinase activity that extends half the length of a sarcomere. It serves as a scaffold to which myofibrils and other muscle related proteins are attached. This gene encodes a protein found in striated and cardiac muscle that binds to the titin Z1-Z2 domains and is a substrate of titin kinase, interactions thought to be critical to sarcomere assembly. Mutations in this gene are associated with limb-girdle muscular dystrophy type 2G. [provided by RefSeq, Jul 2008]

TCAP Gene-Disease associations (from GenCC):

• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 25

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• autosomal recessive limb-girdle muscular dystrophy type 2G

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 17-39665182-G-T is Benign according to our data. Variant chr17-39665182-G-T is described in ClinVar as Benign. ClinVar VariationId is 672043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.684 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003673.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCAP	NM_003673.4	MANE Select	c.-178G>T		upstream_gene	N/A	NP_003664.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCAP	ENST00000309889.3	TSL:1 MANE Select	c.-178G>T		upstream_gene	N/A	ENSP00000312624.2
	TCAP	ENST00000578283.1	TSL:5	c.-178G>T		upstream_gene	N/A	ENSP00000462787.1

Frequencies

GnomAD3 genomes AF: 0.523 AC: 79415 AN: 151982 Hom.: 23693 Cov.: 33

Gnomad AFR AF: 0.227

Gnomad AMI AF: 0.740

Gnomad AMR AF: 0.536

Gnomad ASJ AF: 0.683

Gnomad EAS AF: 0.410

Gnomad SAS AF: 0.703

Gnomad FIN AF: 0.691

Gnomad MID AF: 0.630

Gnomad NFE AF: 0.656

Gnomad OTH AF: 0.554

GnomAD4 exome AF: 0.643 AC: 306672 AN: 477056 Hom.: 101324 Cov.: 5 AF XY: 0.651 AC XY: 164713 AN XY: 252952

African (AFR) AF: 0.231 AC: 3223 AN: 13952

American (AMR) AF: 0.575 AC: 16373 AN: 28476

Ashkenazi Jewish (ASJ) AF: 0.686 AC: 10505 AN: 15310

East Asian (EAS) AF: 0.466 AC: 13986 AN: 29998

South Asian (SAS) AF: 0.740 AC: 38449 AN: 51946

European-Finnish (FIN) AF: 0.682 AC: 19589 AN: 28720

Middle Eastern (MID) AF: 0.709 AC: 1631 AN: 2300

European-Non Finnish (NFE) AF: 0.666 AC: 186249 AN: 279572

Other (OTH) AF: 0.622 AC: 16667 AN: 26782

GnomAD4 genome AF: 0.522 AC: 79433 AN: 152100 Hom.: 23698 Cov.: 33 AF XY: 0.524 AC XY: 38927 AN XY: 74350

African (AFR) AF: 0.226 AC: 9388 AN: 41502

American (AMR) AF: 0.537 AC: 8210 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.683 AC: 2370 AN: 3472

East Asian (EAS) AF: 0.410 AC: 2113 AN: 5154

South Asian (SAS) AF: 0.704 AC: 3404 AN: 4834

European-Finnish (FIN) AF: 0.691 AC: 7320 AN: 10588

Middle Eastern (MID) AF: 0.616 AC: 181 AN: 294

European-Non Finnish (NFE) AF: 0.656 AC: 44604 AN: 67948

Other (OTH) AF: 0.555 AC: 1171 AN: 2110

Alfa AF: 0.625 Hom.: 48645

Bravo AF: 0.496

Asia WGS AF: 0.579 AC: 2015 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.2
DANN	Benign	0.82
PhyloP100		0.046
PromoterAI		-0.024	Neutral
Mutation Taster		=299/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs931992; hg19: chr17-37821435;